Mature T cells expressing the gamma delta T cell receptor are a minor population of peripheral blood lymphocytes but constitute an important mechanism for innate immunity to infectious disease. The largest subpopulation of gammadelta T cells in blood express the Vgamma2/Vdelta2 T cell receptor. During HIV-1 infection the Vgamma2/Vdelta2 T cell count and function declines sharply below normal levels and remains low in the absence of antiretroviral therapy. We hypothesize that decreased numbers and function of Vgamma2/Vdelta2 T cells constitute an innate immunity correlate for HIV-1 disease, and that recovery of gammadelta T cells is a surrogate marker for effective antiretroviral therapy. Our studies will test this hypothesis in cross-sectional and longitudinal studies measuring changes in Vgamma2/Vdelta2 T cells during HIV infection and therapy. Based on preliminary data suggesting that interferon-alpha suppresses gammadelta T cell responses to model antigens, we will examine effects of this cytokine as a potential mechanism for the profound gammadelta T cell loss during untreated HIV infection. Three Specific Aims describe our work: Specific Aim I: Test the hypothesis that Vgamma2-Jgamma1.2/Vdelta2 T cells are selectively depleted during HIV infection Specific Aim II: Test the hypothesis that increased Vgamma2-Jgamma1.2/Vdelta2 T cell count and function are surrogate markers of effective antiretroviral therapy. Specific Aim III: Test the hypothesis that interferon-alpha promotes activation-induced death in Vgamma2/Vdelta2 T cells. Our long term goals are to confirm or disprove the relationships between changing Vgamma2/Vdelta2+ T cell populations and HIV disease progression. The gammadelta T cells are important components of innate immunity and may be a renewable T cell resource after HIV infection. With further study of these unusual T cells, we may find clinical situations that encourage the development of immunotherapy directed specifically at the gammadelta population. Finally, the patterns of gammadelta T cell depletion and reconstitution afford an excellent opportunity to study mechanisms for depleting uninfected bystander cell populations. These indirect mechanisms likely have substantial impact on disease progression, and additional work in this area will help to highlight special mechanisms that render HIV a difficult target for therapies and vaccines.